2,6-diamino-6-methyl-heptanoic acid and derivatives, process for the preparation thereof and use thereof

ABSTRACT

The present invention is directed towards compounds of the general formula (I)  
                 
 
     (I) are important intermediates for the preparation of pharmaceuticals.  
     Further intermediates, process for the preparation of (I) and use thereof.

[0001] The present invention is directed towards compounds of thegeneral formula (I)

[0002] The invention also describes intermediates of (I), a process forthe preparation thereof and the use thereof. Compounds of formula (I)are suitable intermediates for the preparation of pharmaceuticalsdescribed in U.S. Pat. No. 5,552,397, WO 9738705 and in J. Med. Chem.42, 305 (1999).

[0003] In J. Med. Chem. 42, 305 (1999), a synthesis route for thepreparation of a structural unit—an α-amino-ε-caprolactam derivative—ofthe pharmaceutically active compounds is mentioned. That structural unitis obtained with the aid of expensive reagents in a process that israther disadvantageous for a robust commercial process.

[0004] Accordingly, the object was to provide other precursors for thepreparation of α-amino-ε-caprolactam derivatives, and to provide aprocess for the preparation thereof. In particular, the process is to besuitable for use on a commercial scale, that is to say advantageous froman ecological and economic point of view.

[0005] The object is achieved by compounds of the general formula (I)

[0006] wherein

[0007] R¹, R¹ each independently of the other represents H,(C₁-C₈)-acyl, (C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyloxycarbonyl,(C₆-C₁₈)-aryloxycarbonyl, (C₇-C₁₉)-aralkyloxycarbonyl,(C₃-C₁₈)-heteroaryloxycarbonyl, (C₄-C₁₉)-heteroaralkyloxycarbonyl,(C₃-C₈)-cycloalkylcarbonyl, (C₆-C₁₈)-arylcarbonyl,(C₇-C₁₉)-aralkylcarbonyl, (C₃-CO₈)-heteroarylcarbonyl,(C₄-C₁₉)-heteroaralkylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkyloxycarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-aryloxycarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroaryloxycarbonyl, ((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkylcarbonyl, ((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-arylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroarylcarbonyl, or an N-protectinggroup, such as, for example, formyl, Fmoc, t-Boc, Z,

[0008] R³ represents OH, NH₂, O—(C₁-C₈)-alkyl, NH—(C₁-C₈)-alkyl,N((C₁-C₈)-alkyl)₂, O—(C₃-C₈)-cycloalkyl, NH—(C₃-C₈)-cycloalkyl,N((C₃-C₈)-cycloalkyl)₂, O—(C₆-C₁₈)-aryl, NH—(C6-C₁₈)-aryl,N((C₆-C₁₈)-aryl)_(2, O—(C) ₇-C₁₉)-aralkyl, NH—(C₇-C₁₉)-aralkyl,N((C₇-C₁₉)-aralkyl)₂,

[0009] or R² and R³ form a ring via a —CO—NH— group,

[0010] R⁴, R⁵ each independently of the other represents H,(C₁-C₈)-acyl, (C₃-C₈)-cycloalkylcarbonyl, (C₆-C₁₈)-arylcarbonyl,(C₇-C₁₉)-aralkylcarbonyl, (C₃-C₁₈)-heteroarylcarbonyl,(C₄-C₁₉)-heteroaralkylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-arylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroarylcarbonyl, formyl,

[0011] R⁶, R⁷ each independently of the other represents (C₁-C₈)-alkyl,(C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl,(C₇-C₁₉)-aralkyl, (C₃-C₁₈)-heteroaryl, (C₄-C₁₉)-heteroaralkyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkyl, ((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-aryl, ((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroaryl, or the tworadicals are bonded to one another via a (C₁-C₈)-alkylene bridge.

[0012] Compounds of the general formula (I) can readily be convertedinto the desired α-amino-ε-caprolactam derivatives by processes known tothe person skilled in the art, whereby a novel approach to obtainingthat class of compounds has been opened up.

[0013] Preference is given to compounds of the general formula (I)wherein

[0014] R¹ represents H,

[0015] R² represents an N-protecting group, especially t-Boc, Z,

[0016] R³ represents OH, NH₂, O—(C₁-C₈)-alkyl, NH— (C₁-C₈)-alkyl,

[0017] R⁴ represents H, R⁵ represents (C₁-C₈)-acyl,

[0018] R⁶, R⁷ represent (C₁-C₈)-alkyl.

[0019] Also preferred are compounds of the general formula (I) in whichR¹, R²=H, R³=OH, R⁶, R⁷=methyl, R⁴, R⁵=H or R⁴=H, R⁵=formyl, or R⁴=H,R⁵=acetyl.

[0020] In a further embodiment, the invention relates to compounds ofthe general formula (II)

[0021] wherein R¹ ₁ R², R³, R⁶, R⁷ may be as defined above. Preferenceis given to compounds of the general formula (II) wherein R¹, R²=H andR³=OH or NH₂ and R⁶, R⁷=methyl. Also preferred are compounds of thegeneral formula (II) wherein R¹=H, R²=acetyl and R³=OH and R⁶ ₁R⁷=methyl. Also advantageous are compounds of the general formula (II)wherein R¹=H and R² and R³ form a ring via a —CO—NH—group, and R⁶,R⁷=methyl.

[0022] In another aspect, the invention is concerned with compounds ofthe general formula (III)

[0023] wherein R¹, R² R³ R⁶ R⁷ may be as defined above, and R¹, R² arenot phthaloyl when R³=Obenzyl and R⁶, R⁷=methyl. Preference is given tocompounds of the general formula (III) wherein R¹, R²=H and R³=OH or NH₂and R⁶, R⁷=methyl. Also preferred are compounds of the general formula(III) wherein R¹=H, R²=acetyl and R³=OH and R⁶, R⁷=methyl. Alsoadvantageous are compounds of the general formula (III) wherein R¹=H andR² and R³ form a ring via a —CO—NH— group, and R⁶, R⁷=methyl.

[0024] In a further aspect, the invention is concerned with compounds ofthe general formula (IV)

[0025] wherein R⁶ ₁ R⁷ may have the meanings mentioned at the beginningfor those radicals and R⁸ represents NH₂ or OH. R⁶, R⁷ preferablyrepresent methyl.

[0026] In yet a further aspect, the invention is directed towardscompounds of the general formula (V)

[0027] wherein

[0028] each of R¹, R², R⁶, R⁷ may be as defined at the beginning, andR¹⁰, R¹¹ may represent (C₁C₈ )-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl,(C₃-C₁₈)-heteroaryl, (C₄-C₁₉)-heteroaralkyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkyl, ((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-aryl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroaryl In (V), preferably R¹=H andR²=acetyl and R¹⁰, R¹¹=methyl or ethyl and R⁶, R⁷=methyl.

[0029] In a particular embodiment, the present invention relates to aprocess for the preparation of compounds of the general formula (I). Theprocess is distinguished by the fact that compounds of the generalformula (II) or of the general formula (III)

[0030] wherein R¹, R², R³, R⁶, R⁷ may be as defined at the beginning,are reacted under acid conditions with a nitrile. Such a reaction, knownas the Ritter reaction (Org. React. 17, 213-326 (1969)), makes itpossible to obtain the substances of the general formula (I) in a highyield starting from the readily accessible compounds (II) or (III). Theconditions under which the reaction takes place are in principlesufficiently well known to the person skilled in the art (Org. React.17, 213-326 (1969)). More advantageously, however, the reaction iscarried out in strongly acid media, preferably in from 65 to 85%sulfuric acid. The temperature in the reaction is on the one hand to besufficiently high that the reaction proceeds sufficiently rapidly. Onthe other hand, however, it should not be chosen to be so high that thereactants are destroyed. A temperature range from −20 to 100° C. istherefore preferred, with the range from 20 to 40° C. being especiallypreferred. There may be used as nitrites all compounds that come intoconsideration to the person skilled in the art for that purpose.Preferred nitriles are those that are readily available commercially.Hydrocyanic acid, acetonitrile or benzonitrile are especially preferred.The use of hydrocyanic acid is very especially preferred. For thereaction with the nitrile, special preference is given to an N-acetylderivative, an amide, a hydantoin of (II) or (III) or the free aminoacids of (II) or (III).

[0031] The N⁶-acyl derivatives obtained by the reaction with nitritescan be converted into the corresponding compounds having a free aminogroup by hydrolysis. Hydrolysis of the N-formyl compound resulting fromthe reaction with hydrocyanic acid proceeds in an especially simplemanner. Hydrolysis of the N⁶-acyl derivatives is preferably carried outwithout isolation of those compounds. To that end, the reaction mixtureof the Ritter reaction is diluted with water and stirred until theacetyl compound is hydrolysed completely. The amount of water added ispreferably such that a from 10 to 50% sulfuric acid solution results.The hydrolysis is preferably carried out at from 20 to 150° C., veryespecially preferably at from 50 to 100° C.

[0032] The N⁶-acyl derivatives of formula (I) obtained by the reactionwith nitrites may also be converted directly into the correspondingesters having a free amino group by alcoholysis. Alcoholysis of theN-formyl compound resulting from the reaction with hydrocyanic acidproceeds in an especially simple manner.

[0033] The resulting compounds of the general formula (I) can bepurified by processes known to the person skilled in the art. In thecase where a free amino group is present in (I), an especially suitablemethod of purification is strongly acid ion-exchange chromatography.Working up of the compound (I) obtained in the Ritter reaction ispreferably effected by diluting the reaction mixture with water and thenapplying it directly to a strongly acid ion exchanger. The sulfuricacid, which may optionally be used again after concentration, is removedby elution with water, while the amino acid is bonded to the ionexchanger. Elution with dilute ammonia then yields the pure amino acid.The advantage of that process variant is that no salt is formed, whichwould have to be disposed of.

[0034] It is very advantageous to generate the compounds of the generalformula (II) or (III) from compounds of the general formula (IV). Thechemical transformations necessary therefor are sufficiently well knownto the person skilled in the art. In the case where an aminonitrile ofthe formula (IV) is present, it may be saponified analogously to theprocesses known for other amino acids either to the acid (R³ in formula(II)/(III) =OH) or to the amide (R³ in formula (II)/(III)=NH₂).Saponification to the acid can be carried out under either basic or acidconditions. Since side-reactions may optionally occur under acidconditions, it is preferably carried out under basic conditions.Saponification to the amide is preferably carried out at a pH value offrom 11 to 14, preferably from 12.5 to 13.5, in the presence of aketone, preferably acetone (EP 905257). The amide may also be preparedby known processes, for example by aminolysis of alkyl esters.

[0035] The compounds of the general formula (III) can be prepared in avery simple manner from compounds of the general formula (II) byaddition of water to the double bond. That reaction preferably takesplace under acid, aqueous conditions. If such conditions are used in thealready described processes for the preparation of the compounds offormula (II), some or all of the corresponding compounds of the generalformula (III) can be obtained immediately. It is not critical for thepreparation of the compounds of formula (I) whether the alkenes offormula (II) or the alcohols of formula (III) are used for the Ritterreaction.

[0036] It is also preferred to prepare the compound of the generalformula (IV) from the corresponding aldehyde by cyanide addition. Suchcyanhydrin syntheses are known to the person skilled in the art. Thealdehyde may also be converted directly into the aminonitrile of formula(IV) using known processes (Strecker synthesis) by reactions withcyanide compounds, such as, for example, HCN, KCN, NaCN, in the presenceof ammonia. In the case of 5-methyl-4-hexenal, which is highly preferredand can be prepared in a very simple manner from 3-methyl-1-buten-3-oland vinyl ethyl ether (R. Marbet, G. Saucy, Helv. Chimia Acta, 50, 2095(1967)), the reaction takes place with CN ⁻in the presence of ammonia to6-methyl-2-amino-hept-5-enenitrile.

[0037] If the reaction of the corresponding aldehyde with hydrocyanicacid or with cyanide and ammonia is carried out in the presence ofcarbonate, there is obtained the hydantoin of formula (II)/(III) inwhich R¹=H, R² and R³ are bonded together via a —CO—NH— group. Bysaponification of the hydantoin, either the amide or the acid arelikewise accessible.

[0038] Alternatively, the hydantoin may be prepared by reaction of theacid (R³ in formula (II)/(III)=OH) with alkali cyanate, preferablypotassium cyanate. If aqueous, strongly acid conditions are used for thecyclisation of the N-carbamoyl compound formed as an intermediate inthat reaction, then the corresponding hydantoin of the general formula(III) is thus likewise obtained directly.

[0039] Also preferably, the compounds of the general formula (II) or(III) may also be prepared from compounds of the general formula (V).Compound of the general formula (V) may in turn be obtained by reactionof compounds of the general formula (VI)

[0040] in which R⁶, R⁷ may be as defined at the beginning and R⁹represents a customary leaving group and, especially, representsha;pgen, OSO₂CH₃, —OSO₂—C₆H₅—CH₃, with compounds of the general formula(VII)

[0041] wherein R¹, R², R¹⁰,R¹¹ may be as defined above.

[0042] That amino acid synthesis, called the malonic ester route, iswell known to the person skilled in the art (Organikum, VEB-Verlag,Berlin 1986, 418). The compounds of formula (V) obtained by thatreaction wherein, for example, R¹=H, R²=acetyl, R¹⁰ ₁ R¹¹ methyl can beconverted into the corresponding N-acetyl-amino acids of formula (II) or(III) by saponification and subsequent decarboxylation.

[0043] The homoallyl compounds of formula (VI) that are used arepreferably the halogens, which are obtainable in a simple manner, forexample, by reaction of 2-cyclopropyl-2-propanol with magnesium halides(J. P. McCormick, D. L. Barton, J. Org. Chem. 45, 2566 (1980)). Veryspecial preference is given to the use of the bromide.

[0044] Preferred malonic esters of formula (VII) that are used areacetamidomalonic esters (R¹=H, R²=acetyl). The use of diethyl ester(R¹⁰, R¹¹=ethyl) is very especially preferred.

[0045] Moreover, the N-acetyl-amino acids of formula (II) or (III) canalso in principle be prepared directly from the corresponding aldehydesby amidocarbonylation (EP 338330, Angew. Chem., 109, 1534 (1997)).

[0046] In a further embodiment, the invention is concerned with the useof the compounds of the general formulae I, II, III, IV and V in thepreparation of biologically active compounds. In particular, thosecompounds are used preferably in the preparation ofα-amino-ε-caprolactam derivatives.

[0047] As described in J. Med. Chem. 42, 305 (1999), that may beeffected, for example, by cyclisation of the phthaloyl-protected benzylester. According to the present invention it is also possible in asimple manner to use for the cyclisation also other protectedderivatives of formula I, such as, for example, Z, Boc, Fmoc.

[0048] It is also possible to convert the aminonitriles of formula (IV)directly into the corresponding α-amino-ε-caprolactam derivatives, forexample by an intramolecular Ritter reaction. α-Amino-ε-caprolactamderivatives may also be obtained directly from the amides of formula(II) or of formula (III), in which, preferably, R³ represents NH₂,NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, NH—(C₆-C₁₈)-aryl,NH—(C₇-C₁₉)-aralkyl or R² and R³ form a ring via a —CO—NH— group, forexample by reaction under strongly acid conditions (Ritter conditions).

[0049] The chemical structures indicated relate to all possiblestereoisomers that can be achieved by changing the configuration of theindividual chiral centres, axes or planes, that is to say all possiblediastereoisomers, as well as all optical isomers (enantiomers) includedtherein, and also diastereoisomeric mixtures and racemates. Within thescope of the invention, however, it is very especially preferred toprepare the compounds of formula (I) in as high an enantiomericallyconcentrated form as possible. The L-configuration is especiallypreferred. Accordingly, the person skilled in the art is free to use theagents for enantiomeric separation or chiral induction that are known tohim and are suitable for that purpose. The person skilled in the art isalso free to decide at which stage the enantiomeric concentration is tobe achieved. Preferably, however, it will take place as early in thesynthesis as possible so that, optionally, inexpensively prepared wrongenantiomer does not have to be disposed of or, in the case whereracemisation may be possible, losses in yield do not have to be reckonedwith. It depends on each individual case, however.

[0050] Enantiomeric separation may preferably be realised either bycrystallisation or with the aid of enzymes. Enzymatic processes areespecially preferably used therefor.

[0051] Diastereoisomeric salt pairs with chiral acids or bases arepreferably used for racemate cleavage by selective crystallisation (J.P.Greenstein, M. Winitz, “Chemistry of the Amino Acids, Wiley, N.Y., 1961,p. 716). For the formation of salt pairs with chiral acids there arepreferably used the esters (R³=O—(C₁-C₈)-alkyl, O—(C₃-C₈)-cycloalkyl,O—(C₆-C₁₈)-aryl, O—(C₇-C₁₉)-aralkyl) or the amides (R³=NH₂) of thecompounds of formula (I), (II) and (III) in which R¹, R²=H. Theformation of salt pairs with chiral bases is preferably carried out withthe N-acyl compounds of formula (I), (II) and (III) in which R³=OH.

[0052] A further possible method of racemate cleavage consists inseparating suitable derivatives of the amino acid derivatives of formula(I), (II) or (III) by fractional crystallisation (J.P. Greenstein, M.Winitz, “Chemistry of the Amino Acids, Wiley, N.Y., 1961, p. 715).

[0053] For enzymatic racemate cleavage, the esters of (I), (II) or (III)(R³ in formula (I), (II) or (III)=O—(C₁-C₈)-alkyl, O—(C₃-C₈)-cycloalkyl,O—(C₆-C₁₈)-aryl, O—-(C₇-C₁₉)-aralkyl), for example, may be cleavedenantioselectively with enzymes, such as, for example, a-chymotrypsin(“Enzyme catalysis in Organic Chemistry”, ed. K. Drauz, H. Waldmann, VCHWeinheim, 1995, p. 198).

[0054] It is also possible to obtain the desired enantiomers inconcentrated form by oxidation of the undesired enantiomers of the aminoacids of formula (I), (II) or (III) in which R¹, R²=H with the aid ofamino acid oxidases (“Enzyme catalysis in Organic Chemistry”, ed. K.Drauz, H. Waldmann, VCH Weinheim, 1995, p. 774) to the correspondingketo acid.

[0055] A further possible method of preparing both the L- and theD-enantiomers consists in the enzymatic cleavage of the amides (R³ informula (I) (II) or (III)=NH2) with the aid of amidases (“Enzymecatalysis in Organic Chemistry”, ed. K. Drauz, H. Waldmann, VCHWeinheim, 1995, p. 379).

[0056] Enzymatic cleavage of the hydantoins (R², R³ in formula (I), (II)or (III) together form a —CO—NH— ring) with D- or L-hydantoinase alsoyields, after hydrolysis of the resulting N-carbamoyl compounds, theenantiomerically pure amino acids of formula (I), (II) or (III) (“Enzymecatalysis in Organic Chemistry”, ed. K. Drauz, H. Waldmann, VCHWeinheim, 1995, p. 409).

[0057] It is also possible to cleave the N-acylamino acids of formula(I), (II) or (III) (R³, R¹=H, R²=acyl) with acylases (“Enzyme catalysisin Organic Chemistry”, ed. K. Drauz, H. Waldmann, VCH Weinheim, 1995, p.393).

[0058] Enantiomerically concentrated compounds of formula (I) or (II)can be obtained by enantioselective hydrolysis of the aminonitriles offormula (IV) with nitrilases or nitrile hydratases (“Enzyme catalysis inOrganic Chemistry”, ed. K. Drauz, H. Waldmann, VCH Weinheim, 1995, p.367).

[0059] A possible method of shaping the enantioselectivity by chiralinduction consists in the addition of cyanide to the correspondingaldehyde in order to obtain (IV) enantioselectively, for example withthe aid of oxynitrilases (“Enzyme catalysis in Organic Chemistry”, ed.K. Drauz, H. Waldmann, VCH Weinheim, 1995, p. 591) or with the aid ofchiral catalysts (e.g. diketopiperazines (M. North, Synlett, 1993,807)). The enantiomerically concentrated cyanhydrins of formula (IV) soobtainable can be converted stereoselectively into the correspondingaminonitriles (“Enzyme catalysis in Organic Chemistry”, ed. K. Drauz, H.Waldmann, VCH Weinheim, 1995, p. 585).

[0060] The malonic esters of formula (V) can also be converted into theenantiomerically concentrated amino acid derivatives of formula (II) or(III) by enzymatic partial hydrolysis analogously to the processdescribed in EP 812819.

[0061] The L-amino acids of formula (I) required for the preparation ofthe intermediates described in US 5552397, WO 9738705 and in J. Med.Chem. 42, 305 (1999) are preferably prepared by enzymatic cleavage ofthe N-acylamino acids. The cleavage may be carried out, for example,either with 2,6-diamino-6-methylheptanoic acids or with2-amino-6-methyl-5-heptenoic acids or2-amino-6-hydroxy-6-methyl-heptanoic acids. The latter can be convertedinto the former by the reaction with nitrites according to the inventionwithout any loss in optical purity.

[0062] There are preferably used for the acylase cleavage theN-acetylamino acids of formula (I) or (II). The acylase cleavage may becarried out, for example, either with the N⁶-acyl compounds resultingfrom the Ritter reaction or with the corresponding N⁶-deprotectedcompounds. Very special preference is given to the use of theN²-acetylamino acids of formula (II) for the acylase cleavage.

[0063] The enzyme preferably used is an L-acylase, and the reaction iscarried out at a pH value of from 3 to 9, preferably from 5 to 8. Thereare preferably used as base alkali metal hydroxides, very especiallypreferably sodium hydroxide.

[0064] Advantageously, in the case ofN-acyl-2-amino-6-methyl-5-heptenoic acid, 2-amino-6-methyl-5-heptenoicacid precipitates from the reaction medium after the acylase cleavageand can be separated off in a simple manner by filtration.

[0065] Otherwise, the L-amino acids are separated from the unreactedD-acylamino acids preferably by chromatography on ion exchangers. Astrongly acid ion exchanger is preferably used for that purpose. In thatcase, the amino acid and the cations of the base that is used arebonded, while the acylamino acids and the carboxylic acids correspondingto the acyl group can be washed out with water. The amino acid can thenbe eluted selectively, for example with aqueous ammonia.

[0066] The undesired enantiomers formed in the enantiomeric separationcan be racemised by known processes and used again (e.g. racemisation ofamides: EP 905257, EP 442585; racemisation of N-acetylamino acids US4602096). (C₁-C₈)-Alkyl may be regarded as being methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, pentyl,hexyl, heptyl or octyl, including all isomers due to different positionsof the double bond. They may be mono- or poly-substituted by(C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen, NH₂, NO₂, SH,S—(C₁-C₈)-alkyl.

[0067] (C₂-C₈)-Alkenyl is to be understood as being a (C₁-C₈)-alkylradical as described above, with the exception of methyl, that has atleast one double bond.

[0068] (C₂-C₈)-Alkynyl is to be understood as being a (C₁-C₈)-alkylradical as described above, with the exception of methyl, that has atleast one triple bond.

[0069] (C₁-C₈)-Acyl is to be understood as being a (C₁-C₈)-alkyl radicalbonded to the molecule via a -C═O— function.

[0070] (C₃-C₈)-Cycloalkyl is to be understood as being cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals, etc. Theymay be substituted by one or more halogens and/or radicals containing anN, O, P, S atom and/or may have in the ring radicals containing an N, O,P, S atom, such as, for example, 1-, 2-, 3-, 4-piperidyl, 1-, 2-,3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl. They mayalso be mono- or poly-substituted by (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl,OH, Cl, NH2, NO₂.

[0071] A (C₆-C₁₈)-aryl radical is to be understood as being an aromaticradical having from 6 to 18 carbon atoms. Such radicals includeespecially compounds such as phenyl, naphthyl, anthryl, phenanthryl,biphenyl radicals. It may be mono- or poly-substituted by(C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen, NH₂, NO₂, SH,S—(C₁-C₈)-alkyl.

[0072] A (C₇-C₁₉)-aralkyl radical is a (C₆-C₁₈)-aryl radical bonded tothe molecule via a (C₁-C₈)-alkyl radical.

[0073] (C₁-C₈)-Alkoxy is a (C₁-C₈)-alkyl radical bonded to the moleculein question via an oxygen atom.

[0074] (C₁-C₈)-Alkoxycarbonyl is a (C₁-C₈)-alkyl radical bonded to themolecule in question via a —OC(O)—function. The same appliessynonymously to the other oxycarbonyl radicals.

[0075] (C₁-C₈)-Haloalkyl is a (C₁-C₈)-alkyl radical substituted by oneor more halogen atoms.

[0076] Within the scope of the invention, a (C₃-C₁₈)-heteroaryl radicaldenotes a five-, six- or seven-membered aromatic ring system of from 3to 18 carbon atoms that contains hetero atoms such as, for example,nitrogen, oxygen or sulfur in the ring. Such heteroaromatic radicals areto be regarded as being especially radicals such as 1-, 2-, 3-furyl,such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-,3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl,acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl. Itmay be mono- or poly-substituted by (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl,OH, halogen, NH2, NO₂, SH, S—(C₁-C₈)-alkyl.

[0077] A (C₄-C₁₉)-heteroaralkyl is to be understood as being aheteroaromatic system corresponding to the (C₇-C₁₉)-aralkyl radical.

[0078] The expression (C₁-C₈)-alkylene unit is to be understood asmeaning a (C₁-C₈)-alkyl radical that is bonded to the molecule inquestion via two single bonds of its carbon atoms. It may be mono- orpoly-substituted by (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen, NH2,NO₂, SH, S—(C₁-C₈)-alkyl.

[0079] Suitable halogens are fluorine, chlorine, bromine and iodine.

[0080] Within the scope of the invention, the expressionenantiomerically concentrated is to be understood as meaning theproportion of an enantiomer in admixture with its optical antipodes in arange>50% and <100%.

EXAMPLES

[0081] 1. Preparation of D,L-1-amino-5-methyl-4-heptenylnitrile

[0082] 67.76 g of sodium cyanide and 28.4 g of ammonium chloride aredissolved in 210 ml of water and 194 g of 25% aqueous ammonia solution,and heated to 60° C. 71.0 g of 5-methyl-2-hexanal are added dropwise inthe course of 30 minutes, and stirring is then carried out for 1.5 hoursat 60° C. Cooling and extraction with 200 ml of MtBE are then carriedout. Removal of the solvent by distillation yields 77 g of theaminonitrile in the form of an oil.

[0083]¹H-NMR (DMSO): 1.59 (s, 3H), 1.66 (s, 3H), 2.08 (m, 3H), 2.27 (m,2H), 3.62 (m, 1H), 5.09 (m, 1H).

[0084] MS: 139 (M +H+), 112 (M−HCN +H⁺), 95.

[0085] 2. Preparation of D,L-2-amino-6-methyl-5-heptenoic acid

[0086] 696 g of 25% aqueous ammonia solution are added to 168.8 g of5-methyl-2-hexanal, 67.76 g of sodium cyanide, 86.0 g of ammoniumchloride in 510 ml of water, and the whole is heated for 2 hours at 60°C. 300 g of 50% sodium hydroxide solution are then added, and heating iscarried out for 4 hours at reflux. Cooling and extraction with 500 ml ofMIBK are then carried out, and the aqueous phase is concentrated to 850g in vacuo. The pH value is adjusted to 6 using concentratedhydrochloric acid; 300 ml of acetone are added, the solid is filteredoff, and washing with water and acetone are then carried out. Dryingyields 89 g of D,L-2-amino-6-methyl-5-heptenoic acid.

[0087]¹H-NMR (DMSO+HCl): 1.58 (s, 3H), 1.66 (s, 3H), 1.81 (m, 2H), 2.02(m, 1H), 2.12 (m, 1H), 3.82 (m, 1H), 5.04 (masked by H₂0, 1H), 8.50 (s,1H).

[0088] 3. Preparation of N⁶-acetyl-D,L-2,6-diamino-6-methyl-heptanoicacid

[0089] 29.6 g of D,L-2-amino-6-methyl-5-heptenoic acid and 9.74 ml ofacetonitrile are stirred for 14 hours at room temperature in 47 g of 96%sulfuric acid and 7.1 g of water. 100 g of ice and 600 ml of water arethen added. The solution is applied to a column containing 600 ml ofAmberlite 252 C and washed with water. Elution with 5% ammonia yields,after concentration in vacuo and digestion with 300 ml of MIBK, 36.0 gof N⁶-acetyl-D,L-2,6-diamino-6-methyl-heptanoic acid.

[0090]¹H-NMR (DMSO+HC1): 1.20 (s, 6H), 1.28 (m, 1H), 1.39 (m, 1H), 1.62(m, 2H), 1.76 (m, 2H), 1.82 (s, 3H), 3.82 (m, 1H), 7.65 (br.s, 1H), 8.48(br.s, 3H).

[0091] 4. Preparation of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid

[0092] 25 g of D,L-2-amino-6-methyl-5-heptenoic acid are suspended in140 ml of water and adjusted to pH 11 using 50% sodium hydroxidesolution. 18 g of acetic anhydride are then added dropwise at 20-25° C.and the pH value is maintained between 10 and 11 during the addition byaddition of 50% sodium hydroxide solution. Stirring is then carried outfor 15 minutes and the pH value is then adjusted to 2 using concentratedhydrochloric acid. The solid that precipitates is filtered off, washedwith water and dried. 28.1 g ofN-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid are obtained.

[0093]¹H-NMR (DMSO): 1.55 (s, 3H), 1.56-1.72 (m, 2H), 1.65 (s, 3H), 1.84(s, 3H), 1.99 (m, 2H), 4.12 (m, 1H), 5.06 (m, 1H), 8.07 (d, 1H).

[0094] 5. Preparation of L-2-amino-6-methyl-5-heptenoic acid

[0095] 26.6 g of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid aresuspended in 135 ml of water, and the pH value is adjusted to 7.0 byaddition of 50% sodium hydroxide solution. 0.8 g of L-acylase is thenadded, and stirring is carried out for 5 days at room temperature.Removal of the precipitate by filtration and washing with water yield8.8 g of L-2-amino-6-methyl-5-heptenoic acid having a [α]589²⁵ of +32.5°(c=1, 1N HCl) and a D content (chiral GC) of<0.1%.

[0096] 6. Preparation of N,N-diacetyl-L-2,6-diamino-6-methyl-heptanoicacid

[0097] 28.1 g of N⁶-acetyl-D,L-2,6-diamino-6-methyl-heptanoic acid aredissolved in 130 ml of water and adjusted to pH 10 using 50% sodiumhydroxide solution. 14.6 g of acetic anhydride and 50% sodium hydroxidesolution are then added dropwise, with cooling, in such a manner thatthe temperature remains <30° C. and the pH value remains between 10 and11. After stirring for a further 10 minutes, the pH value is adjusted to7 by addition of concentrated hydrochloric acid. A sample of thesolution was concentrated to dryness by evaporation in vacuo.

[0098]¹H-NMR (D₂0): 1.26 (s, 3H), 1.32 (m, 2H), 1.66 (m, 3H), 1.75 (m,1H), 1.92 (s, 3H), 2.03 (s, 3H), 4.12 (m, 1H).

[0099] 7. Preparation of N⁶-acetyl-L-2,6-diamino-6-methyl-heptanoic acid

[0100] a) from L-2-amino-6-methyl-5-heptenoic acid

[0101] 8.3 g of the L-2-amino-6-methyl-5-heptenoic acid from Experiment6 are reacted analogously to Test 3 with 13.2 g of 96% sulfuric acid,2.0 g of water and 2.8 ml of acetonitrile. 11.5 g ofN⁶-acetyl-L-2,6-diamino-6-methyl-heptanoic acid having a [α]589²⁵ of+20.7° (c=1, 1N HC1) and a D content (chiral HPLC) of <0.2% areobtained.

[0102] b) by acylase cleavage ofN,N-diacetyl-L-2,6-diamino-6-methyl-heptanoic acid

[0103] The aqueous solution from Experiment 6 is made up to 300 ml withwater; 2.0 g of L-acylase are added thereto and stirring is carried outfor 4 days at room temperature. The solution is applied to a columncontaining 550 ml of Amberlite 252 C, and the unreactedN,N-diacetyl-D(L)-2,6-diamino-6-methyl-heptanoic acid is eluted withwater. Concentration of the eluate in vacuo yields 48 g. Elution is thencarried out with 5% ammonia. Concentration in vacuo and digestion of thesolid with acetone yield 7.8 g ofN⁶-acetyl-L-2,6-diamino-6-methyl-heptanoic acid having a [α]589²⁵ of+18.0° (c=1, 1N HCl) and a D content (chiral HPLC) of 0.2%.

[0104] 8. Preparation of N⁶-formyl-L-2,6-diamino-6-methyl-heptanoic acid

[0105] 1.9 g of L-2-amino-6-methyl-5-heptenoic acid are added to asolution of 0.56 ml of hydrocyanic acid in 6.0 g of 96% sulfuric acidand 0.9 g of water, and stirring is carried out for 2 hours at roomtemperature. 10 g of ice are then added, and the mixture is made up to70 ml with water. The solution is applied to a column containing 60 mlof Amberlite 252 C and then washed with water. Elution with 5% ammoniayields, after concentration in vacuo and digestion with 30 ml ofacetone, 1.9 g of N⁶-formyl-L-2,6-diamino-6-methyl-heptanoic acid.

[0106]¹H-NMR (DMSO+HCl): 1.22 (s, 6H), 1.30 (m, 1H), 1.43 (m, 1H), 1.62(m, 2H), 1.77 (m, 2H), 3.83 (m, 1H), 7.76 (s, 1H), 7.86 (br.s, 1H), 8.48(br.s, 3H).

[0107] 9. Preparation of L-2,6-diamino-6-methyl-heptanoic aciddihydrochloride

[0108] 1.0 g of N⁶-formyl-L-2,6-diamino-6-methyl-heptanoic acid isheated for 2.5 hours at reflux in 10 ml of 1 N hydrochloric acid. Thereaction mixture is then concentrated in vacuo and dried. 1.3 g ofL-2,6-diamino-6-methyl-heptanoic acid dihydrochloride are obtained.

[0109]¹H-NMR (DMSO): 1.23 (s, 6H), 1.41 (m, 1H), 1.51 (m, 1H), 1.58 (m,2H), 1.79 (m, 2H), 3.83 (m, 1H), 8.21 (br. s, 3H), 8.52 (br. s, 3H),13.6 (br.s, 1H).

[0110] 10. Preparation of D,L-2-amino-6-hydroxy-6-methyl-heptanoic acidhydrochloride

[0111] 1.0 g of D,L-2-amino-6-methyl-5-heptenoic acid is heated for onehour at reflux in 10 ml of water and 3 ml of concentrated hydrochloricacid. The reaction mixture is then concentrated in vacuo; 20 ml of MIBKare added and concentration is again carried out. The solid thatprecipitates is filtered off and dried. 1.2 g ofD,L-2-amino-6-hydroxy-6-methyl-heptanoic acid hydrochloride areobtained.

[0112]¹H-NMR (DMSO): 1.07 (s, 6H), 1.34 (m, 3H), 1.47 (m, 1H), 1.55 (s,1H), 1.78 (m, 2H), 3.82 (m, 1H), 8.48 (br.s, 3H), 13.6 (br.s, 1H).

[0113] 11. Preparation of D,L-5-(4-hydroxy-4-methyl-pentyl)-hydantoin

[0114] 4.72 g of D,L-2-amino-6-methyl-5-heptenoic acid are heated for 2hours at 70-80° C. with 1.7 g of potassium hydroxide and 3.65 g ofpotassium cyanate. The pH is then adjusted to 0.5 using concentratedhydrochloric acid, and stirring is carried out for one hour at roomtemperature. The mixture is then rendered neutral using sodium hydroxidesolution, and the precipitate is filtered off and drying is carried outin vacuo. 2.90 g of D,L-5-(4-hydroxy-4-methyl-pentyl)-hydantoin areobtained.

[0115]¹H-NMR (DMSO): 1.06 (s, 6H), 1.33 (m, 4H), 1.49 (m, 1H), 1.62 (m,1H), 3.98 (m, 1H), 4.07 (s, 1H), 7.90 (br.s, 1H), 10.52 (br.s, 1H).

[0116] 12. Preparation of acetamido-(4-methyl-3-pentenyl)-malonic aciddiethyl ester

[0117] 27.1 g of acetamidomalonic acid diethyl ester are heated for 14hours with 19.6 g of 5-bromo-2-methyl-2-pentene and 16.6 g of potassiumcarbonate in 100 ml of MIBK in a water separator. The reaction solutionwas extracted with 100 ml of water, and the organic phase wasconcentrated in vacuo. LC-MS analysis of the residue shows that it is amixture of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid ethyl ester(M+H⁺=228) and acetamido-(4-methyl-3-pentenyl)-malonic acid diethylester (M +H+=300) in a ratio of 3:2.

[0118] 13. Preparation of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acidfrom acetamido-(4-methyl-3-pentenyl)-malonic acid diethyl ester

[0119] A sample of the mixture obtained in Experiment 12 is heated for14 hours at reflux with 10 g of 50% sodium hydroxide solution in 120 mlof water and 100 ml of ethanol. HPLC then shows thatN-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid has formed.

[0120] 14. Cyclisation of D,L-1-amino-5-methyl-4-heptenylnitrile

[0121] 0.10 g of D,L-1-amino-5-methyl-4-heptenylnitrile is stirred for14 hours in 0.32 g of 96% sulfuric acid and 0.05 g of water. LC-MSanalysis of the reaction mixture diluted with water shows for the mainpeak an MS with 157 (M+H⁺) and 112.

[0122] 15. Cyclisation of D,L-5-(4-hydroxy-4-methyl-pentyl)-hydantoin

[0123] 1.6 g of D,L-5-(4-hydroxy-4-methyl-pentyl)-hydantoin are stirredfor 14 hours at room temperature with 0.42 ml of acetonitrile in 4.0 gof 96% sulfuric acid and 0.6 g of water. 20 ml of water are then added,and the pH value is adjusted to 7 using 50% sodium hydroxide solution.The solid that precipitates is filtered off and dried. 0.51 g of2,2-dimethyl-1,7-diaza-bicyclo[4,2,l]nonane-1,7-dione is obtained.

[0124]¹H-NMR (DMSO): 1.22 (s, 3H); 1.27 (m, 1H), 1.39 (m, 1H), 1.50 (m,1H), 1.57 (s, 3H), 1.64 (m, 2H), 1.95 (m, 1H), 4.03 (dd, 1H), 10.44(br.s, 1H).

[0125] 16. Preparation of L-2,6-diamino-6-methyl-heptanoic acid methylester dihydrochloride

[0126] 0.5 g of N⁶-formyl-L-2,6-diamino-6-methyl-heptanoic acid isstirred for 14 hours at room temperature in 10 ml of methanol with 0.45g of thionyl chloride and then heated for 2 hours at 60° C.Concentration of the reaction mixture and drying of the residue in vacuoyield 0.65 g of L-2,6-diamino-6-methyl-heptanoic acid methyl esterdihydrochloride

1. Compounds of the general formula (I)

wherein R¹, R² each independently of the other represents H,(C₁-C₈)-acyl, (C₁-C₈)-alkoxycarbonyl, (C₃-C₈)-cycloalkyloxycarbonyl,(C₆-C₁₈)-aryloxycarbonyl, (C₇-C₁₉)-aralkyloxycarbonyl,(C₃-C¹⁸)-heteroaryloxycarbonyl, (C₄-C₁₉)-heteroaralkyloxycarbonyl,(C₃-C₈)-cycloalkylcarbonyl, (C₆-C₁₈)-arylcarbonyl,(C₇-C₁₉)-aralkylcarbonyl, (C₃-C₁₈)-heteroarylcarbonyl,(C₄-C₁₉)-heteroaralkylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkyloxycarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-aryloxycarbonyl,((C₁-C₈)-alkyl₁₋₃-(C₃-C₁₈)-heteroaryloxycarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-arylcarbonyl, ((C₁-C₈)-alkyl)_(1-3-(C)₃-C18)-heteroarylcarbonyl, or an N-protecting group, such as, forexample, formyl, Fmoc, t-Boc, Z, R³ represents OH, NH₂, O—(C₁-C₈)-alkyl,NH—(C₁-C₈)-alkyl, N((C₁-C₈)-alkyl)₂, O—(C₃-C₈)-cycloalkyl,NH—(C₃-C₈)-cycloalkyl, N((C₃-C₈)-cycloalkyl)₂, O—(C₆-C₁₈)-aryl,NH—(C₆-C₁₈)-aryl, N((C₆-C₁₈)-aryl)₂, O—(C₇-C₁₉)-aralkyl,NH—(C₇-C₁₉)-aralkyl, N((C₇-C₁₉)-aralkyl)₂, or R² and R³ form a ring viaa —CO—NH— group, R⁴, R⁵ each independently of the other represents H,(C₁-C₈)-acyl, (C₃-C₈)cycloalkylcarbonyl, (C₆-C₁₈)-arylcarbonyl,(C₇-C₁₉)-aralkylcarbonyl, (C₃-C₁₈)- heteroarylcarbonyl,(C₄-C₁₉)-heteroaralkylcarbonyl, ((C₁-C₈)-alkyl) 1-3-(C₃-C₈)-cycloalkylcarbonyl, ((C₁-C₈)-alkyl)₁₋₃-(C₆-C₁₈)-arylcarbonyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroarylcarbonyl, formyl, R⁶, R⁷ eachindependently of the other represents (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl,(C₃-C₁₈)-heteroaryl, (C₄-C₁₉)-heteroaralkyl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₈)-cycloalkyl, ((C₁-C₈)-alky)₁₋₃-(C₆-C₁₈)-aryl,((C₁-C₈)-alkyl)₁₋₃-(C₃-C₁₈)-heteroaryl, or the two radicals are bondedto one another via a (C₁-C₈)-alkylene bridge.
 2. Compounds according toclaim 1, wherein R¹ represents H, R² represents an N-protecting group,especially t-Boc, Z, R³ represents OH, NH₂, O—(C₁-C₈)-alkyl,NH—(C₁-C₈)-alkyl, R⁴ represents H, R⁵ represents (C₁-C₈)-acyl, R⁶, R⁷represent (C₁-C₈)-alkyl.
 3. Compounds according to claim 1, in which R¹,R²=H, R³=OH, R⁶, R⁷=methyl, R⁴, R⁵=H or R⁴=H, R⁵=formyl, or R⁴=H,R⁵=acetyl.
 4. Compounds of the general formula (II)

wherein R¹, R R³, R⁶, R⁷ may be as defined according to claims 1 to 3.5. Compounds according to claim 4, wherein R¹, R²=H and R³=OH or NH₂ andR⁶, R⁷=methyl.
 6. Compounds according to claim 4, wherein R¹=H, R²acetyl and R³=OH and R⁶, R⁷=methyl.
 7. Compounds according to claim 6,wherein R¹=H and R² and R³ form a ring via a —CO—NH— group and R⁶,R⁷=methyl.
 8. Compounds of the general formula (III)

wherein R¹, R², R³, R⁶, R⁷ may be as defined according to claims 1 to 3,and R¹, R² are not phthaloyl when R³=Obenzyl and R⁶, R⁷=methyl. 9.Compounds according to claim 8, wherein R¹, R²=H and R³=OH or NH₂ andR⁶, R⁷=methyl.
 10. Compounds according to claim 8, wherein R¹=H,R²=acetyl and R³=OH and R⁶, R⁷=methyl.
 11. Compounds according to claim10, wherein R¹=H and R² and R³ form a ring via a —CO—NH— group, and R6,R⁷=methyl.
 12. Compounds of the general formula (IV)

wherein R⁶, R⁷ may be as defined according to claims 1 to 3 and R⁸represents NH₂ or OH, R⁶, R⁷ preferably represent methyl.
 13. Compoundsof the general formula (V)

wherein R¹, R², R⁶, R⁷ may be as defined in claims 1 to 3 and R¹⁰, R¹¹may represent (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₈)-cycloalkyl, (C₆-C₁₈)-aryl, (C₇-C₁₉)-aralkyl,(C₃-C₁₈)-heteroaryl, (C₄-C₁₉)-heteroaralkyl, ((C₁-C₈)-alkyl) 1-3-(C₃-C₈)-cycloalkyl, ((C₁-C₈)-alkyl) 1-3- (C₆-C₁₈)-aryl, ((C₁-C₈)-alkyl)1-3-(C₃-C₁₈)-heteroaryl.
 14. Compounds according to claim 13, whereinR¹=H and R²=acetyl and R¹⁰, R¹¹=methyl or ethyl and R⁶, R⁷=methyl. 15.Process for the preparation of compounds according to claim 1,characterised in that compounds of the general formula (II) or (III),

wherein R¹, R², R³, R⁶, R⁷ may be as defined according to claims 1 to 3,are reacted under acid conditions with a nitrile.
 16. Process accordingto claim 15, characterised in that the reaction is carried out in from65 to 85% sulfuric acid.
 17. Process according to claim 15 and/or 16,characterised in that the reaction is carried out at a temperature offrom 20 to 40° C.
 18. Process according to claim 15, 16 and/or 17,characterised in that hydrocyanic acid, acetonitrile or benzonitrile areused as the nitriles.
 19. Process according to claim 15, characterisedin that the compounds of the general formula (II) or (III) are generatedfrom compounds of the general formula (IV).
 20. Process according toclaim 19, characterised in that the compound of the general formula (IV)is obtained from the corresponding aldehyde by cyanide addition. 21.Process according to claim 15, characterised in that the compounds ofthe general formula (II) or (III) are generated from compounds of thegeneral formula (V).
 22. Process according to claim 20, characterised inthat the compound of the general formula (V) is obtained by reaction ofcompounds of the general formula (VI)

in which R⁶ R⁷ may be as defined at the beginning and in which R⁹especially represents halogen, OSO₂CH₃, -OSO₂-C₆H₅-C₆H₃, with compoundsof the general formula (VII)

wherein R¹, R², R¹⁰, R¹¹ may be as defined in claims 1 to 3, 13 and 14.23. Use of the compounds of the general formulae I, II, III and IV and Vin the preparation of biologically active compounds.
 24. Use accordingto claim 23 in the preparation of α-amino-ε-caprolactam derivatives. 25.Use according to claim 23, characterised in that the compounds offormula (IV) are converted directly into α-amino-ε-caprolactamderivatives.
 26. Use according to claim 23, characterised in thatα-amino-ε-caprolactam derivatives are obtained directly from the amidesof formula (II) or of formula (III).
 27. Use according to claim 26,characterised in that in (II) or (III), R³ represents NH₂,NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, NH—(C₆-C₁₈)-aryl,NH—(C₇-C₁₉)-aralkyl or R² and R³ form a ring via a —CO—NH— group.